The demonstration that the drugs rolipram and forskalin reverse the inhibition of LTP induced by alpha beta in hippocampal slices and that exposure of cultured hippocampal neurons to alpha beta causes changes in expression of genes involved in the switch from early to late LTP suggests that the cAMP signaling pathway may be an early target of damage in Alzheimer's disease as well as a therapeutic target, The first portion of work proposed will examine the role of alpha beta on the regulation of cAMP levels and investigate the mechanism of alpha beta Down regulation of PKA activity. Emphasis will be on the regulation of levels of the regulatory subunits of PKA. Experiments of APP Tg mice will examine the mechanism of LTP inhibition in the animals and determine if rolipram and forskalin reverse this inhibition. The second portion of the application examines the role of caspase 2 in cellular responses to alpha beta and will explore the issue of whether caspase 2 is necessary for the synaptic loss in APP Tg mice by crossing these animals with caspase 2 null mice.